Relayed signaling between mesenchymal progenitors and muscle stem cells ensures adaptive stem cell response to increased mechanical load
Relayed signaling between mesenchymal progenitors and muscle stem cells ensures adaptive stem cell response to increased mechanical load
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DOI：
10.1016/j.stem.2021.11.003
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发表时间：
2022-02-03
期刊：
影响因子：
23.9
通讯作者：
Fukada, So-ichiro
中科院分区：
文献类型：
--
作者：
Kaneshige, Akihiro;Kaji, Takayuki;Fukada, So-ichiro
对机械负荷的适应，导致力量和功率输出的增强，是骨骼肌的特征。有效的肌肉肥大所需的新肌核的形成依赖于肌肉干细胞(MuSCs)的事先激活和增殖。然而，在负荷增加的情况下，控制MUSC膨胀的机制还不完全清楚。在这里，我们展示了间质间充质祖细胞对机械负荷的反应，并在肌肉负荷增加的外科小鼠模型中刺激骨髓间充质干细胞增殖。从机制上讲，间充质祖细胞中YAP1/带有PDZ结合基序的转录共激活因子(Taz)的转录激活导致局部产生血栓反应蛋白-1(Thbs1)，进而通过CD47信号促进骨髓间充质干细胞的增殖。然而，在动态平衡条件下，CD47信号不足以促进MUSC的增殖，而是依赖于先前降钙素受体的下调。我们的结果表明，间充质祖细胞和MUSCs之间通过YAP1/Taz-Thbs1-CD47通路传递的信号对于建立肌肉肥大期间MUSCs的供应至关重要。
Adaptation to mechanical load, leading to enhanced force and power output, is a characteristic feature of skeletal muscle. Formation of new myonuclei required for efficient muscle hypertrophy relies on prior activation and proliferation of muscle stem cells (MuSCs). However, the mechanisms controlling MuSC expansion under conditions of increased load are not fully understood. Here we demonstrate that interstitial mesenchymal progenitors respond to mechanical load and stimulate MuSC proliferation in a surgical mouse model of increased muscle load. Mechanistically, transcriptional activation of Yes-associated protein 1 (Yap1)/transcriptional coactivator with PDZ-binding motif (Taz) in mesenchymal progenitors results in local production of thrombospondin-1 (Thbs1), which, in turn, drives MuSC proliferation through CD47 signaling. Under homeostatic conditions, however, CD47 signaling is insufficient to promote MuSC proliferation and instead depends on prior downregulation of the Calcitonin receptor. Our results suggest that relayed signaling between mesenchymal progenitors and MuSCs through a Yap1/Taz-Thbs1-CD47 pathway is critical to establish the supply of MuSCs during muscle hypertrophy.